We describe a patient with KS confirmed by molecular study, suffering from recurrent respiratory infections due to left lung anomalies.
The patient carries a 11 bases deletion in the exon 11 of the MLL2 gene, which consists of 54 exons. This deletion determines a frameshift and a stop codon 10 nucleotides downstream from this site. The mutation product is a truncated protein with highly probable loss of function. However we cannot rule out the possibility that this mutation result in the degradation of partial or total transcripts due to nonsense-mediated mRNA decay (NMD), thus contributing to MLL2 protein haploinsufficiency. This specific deletion has not been previously described, but its effect can be compared with other frameshift and with non-sense mutations. The patient described carrying a truncating mutation of MLL2 presented a complex heart defect (interventricular septal disorder and aortic coarctation), as previously reported in the literature .
KS main features are intellectual disability, post-natal growth delay and peculiar facial appearance. The patient herein described showed microcephaly, dysmorphic features (long palpebral fissures, eyebrows with sparse lateral third, everted lower eyelids, blue sclerae, large dysplastic ears, lower lip pits), persistent fetal fingertip pads, short stature, heart defects (interventricular defect and aortic coarctation) and genitourinary malformation, leading to a score of 6 according to Makrythanasis et al. . In addition, neonatal hypoglycemia, not usually detected in this syndrome, was observed in the patient.
Although respiratory infections are frequent in KS , and possibly due to immune system dysfunction, immunological studies showed normal data in our patient. The recurrent and severe bronchitis caused multiple hospitalizations, leading to a worsening of the patient’s life quality. The chest CT scan performed with iv injection of iodine contrast agent showed left bronchial isomerism and several bronchiectasies. Bronchial isomerism is a rare congenital abnormality defined as the absence of the normal lateralizing features which distinguish right and left-sided in the lungs. The morphology of the bronchial tree is defined on the basis of: the length of the main bronchus, the course of pulmonary artery on the bronchus and the number of lobes in the lung . Thus, the left bronchial isomerism is characterized by a long main bronchus, two hyparterial bronchi, two bi-lobed lungs. The atrial arrangement frequently follows that of the bronchial tree . Two patients with KS were diagnosed with an anomalous course of the left pulmonary artery whereas a morphological alteration of the bronchial disposition was not investigated [17, 18]. Left isomerism may be associated with malrotation of abdominal viscera, polysplenia and congenital heart disease . In our patient an echocardiogram confirmed normal atrial arrangement and an abdominal ultrasound scan showed normal data with no spleen anomalies. Several patients with bronchial isomerism present with severe respiratory injuries, such as: recurrent episodes of coughing, wheezing, asthma and bronchiectasies. In particular three patients diagnosed with severe asthma, classified as resistant to high-dose corticosteroid therapy, were found to have left bronchial isomerism [13, 16, 19]. With the detection of left-bronchial isomerism in our patient, in order to prevent his recurrent pulmonary infections, aggressive antibiotic combination together with a regular chest physiotherapy was started, improving his respiratory performances.
Although the genetic basis of heterotaxy remains largely unknown, recently several genes have been recognized in the pathogenesis of this malformation. In particular, SHROOM3 gene has been associated with heterotaxy syndrome; it encodes a cytoskeleton protein responsible for cellular shape during morphogenesis and it has been proposed as a good candidate for the control of left-right (LR) patterning. One of SHROOM3 downstream effectors is Rho Kinase 2 (ROCK2) involved in the proper specification of LR asymmetry during embryonic development . ROCK2 pathway mediates several cellular functions such as cell shape modification, migration and proliferation, through the phosphorylation of different actin dependent targets [21, 22]. Interestingly MLL2 has been shown to interact with both SHROOM3 and ROCK2 proteins. On the basis of these data we suggest that patients with MLL2 deficiency and recurrent respiratory infections should be investigated for defects of lateralization.